Host Response to SARS-CoV-2

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1		Nikola Stojanovic	--	1086	2022-11-28 13:53:11	\|
2	format correct	Conner Chen	Meta information modification	1086	2022-11-29 09:36:26	\|

This entry is adapted from the peer-reviewed paper 10.3390/medicina58111686

The massive expansion of the new coronavirus SARS-CoV-2 has urged countries to introduce lockdowns and set restrictive actions worldwide. When viruses attach to host receptors they penetrate into host cells by fusing with their membrane through endocytosis.

anti-inflammatory antioxidant COVID-19 immunity

1. Introduction

In December 2019, the world was affected by the pandemic, which began with bouts of acute atypical respiratory disease in the city of Wuhan in the Hubei province of China. This rapidly spread from Wuhan to other areas, resulting in a human tragedy and tremendous economic damage. It was soon discovered that the culprit was a new coronavirus, a positive-sense single-stranded RNA virus ^[1]^[2]. It was identified as acute respiratory syndrome coronavirus 2, or SARS-CoV-2, and later renamed Coronavirus Disease-19 or COVID-19 ^[3].

At the beginning, it was thought that the onset of SARS-CoV-2 appeared via a zoonotic spread linked to the seafood market in Wuhan, China. It was then acknowledged that human-to-human dissemination was the real way the outbreak occurred ^[4]. COVID-19 was then determined to be a pandemic by the World Health Organization (WHO). Because of the rapid spread of COVID-19, countries worldwide embraced various restrictive measures aimed at stopping its transmission, including wearing masks, frequent hand washing, and social distancing ^[5]. With regard to social distancing, businesses, schools, community centers, and non-governmental organizations were forced to shut down, public meetings were banned, and restrictive measures were introduced worldwide, allowing travel for essential purposes only. The aim of all these restrictive measures was to enable countries to “flatten the curve” and avoid the collapse of their health-care systems ^[4].

SARS-CoV-2 virus symptoms can range from mild symptoms to critical respiratory insufficiency, with multiple organ dysfunction. The mean incubation period is 5.2 days. On a computerized tomography (CT) scan, the typical pulmonary ground-glass opacification can be found, even in patients who have no symptoms ^[6]. Since the virus predominantly attacks the respiratory system, it can cause fever, dry cough, sore throat, runny nose, and difficulty breathing ^[7]. Other organ systems can also be affected, causing symptoms, such as headache, dizziness, generalized weakness, vomiting, and diarrhea ^[8]. COVID-19-induced respiratory symptoms can vary greatly, extending from mild symptoms to severe shortness of breath and acute respiratory failure. In a report from Wuhan, the time between the appearance of symptoms and the development of acute respiratory insufficiency was only 9 days, suggesting that the respiratory symptoms may develop quickly and be severe. In addition, this virus could also be fatal ^[7].

Epidemiological data have demonstrated that mortalities were increased among the elderly ^[9] and that incidence was decreased among children ^[3]. Knittel and Ozaltun ^[10] documented a positive correlation between the number of the elderly, the incidence of commuting using community transport, and the frequency of SARS-Cov-2-induced deaths in the US. On the other hand, the authors provided evidence that obesity rates, intensive-care-unit beds per capita, and poverty rates were not linked to the lethality rate. The ongoing therapeutic solution is mainly supportive, with no identified and definite treatment obtainable yet.

2. Structure of SARS-CoV-2: Mechanism of SARS-CoV-2 Invasion into Host Cells

Coronaviruses are largely divided into four genera: α, β, γ, and δ, all based on their genomic structure, where α and β coronaviruses only infect mammals. At the moment, SARS-CoV-2 is classified as a β coronavirus ^[11].

The life cycle of the virus inside the host involves the following five steps: attachment, penetration, biosynthesis, maturation, and release. When viruses attach to host receptors they penetrate into host cells by fusing with their membrane through endocytosis. When viral RNA is incorporated into the nucleus, the process of replication begins and the virus makes its own proteins and releases its particles outside of the cell. Coronaviruses have four structural proteins: spike (S), membrane (M), envelope (E), and nucleocapsid (N) ^[12]. It has been found that SARS-CoV-2 has a functional and attachment affinity towards receptor ACE2, whose expression is high on the apical side of lung epithelial cells. The spike protein binds to ACE2 and after that undergoes a protease cleavage ^[13]. In order to establish whether or not it has another receptor it can bind to, further research needs to be conducted.

3. Host Response to SARS-CoV-2

Since ACE2 is highly expressed on the apical side of lung epithelial cells in the alveolar space ^[14], this virus is likely to penetrate and damage them, even causing apoptosis. T-cell responses induced by COVID-19 are initiated by antigen presentation via dendritic cells and macrophages (which belong to antigen-presenting cells—APCs). These APCs can either phagocytize apoptotic cells infected by the virus ^[15] or are infected by the virus on their own. This question remains unclear, because ACE2 receptors are barely present on dendritic cells and macrophages, so further studies are needed to find out if SARS-CoV-2 uses another receptor to bind to cells.

Immunological research was mainly conducted on adult COVID-19 patients with critical disease, showing lymphopenia and depletion of T lymphocytes ^[9]^[16]. These patients were found out to have elevated levels of pro-inflammatory cytokines, including IL-6, IL-10, GM-CSF, MCP1, MIP1α, and TNF-α ^[7]^[9]^[16]. The more critical the state patients were in, the more increased their serum IL-6 levels were. Depletion of T lymphocytes could be the reason why their disease advanced. Another discovery was that abnormal pathogenic CD4+T lymphocytes expressing both IFN-γ and GM-CSF were found in COVID-19 patients with harsh illness ^[9]. Although GM-CSF was found to help innate immune cells to develop into T cells, it can also be responsible for massive tissue destruction ^[17].

Research shows that respiratory cells attacked by coronavirus generate IL-8 (as well as IL-6) ^[18], which acts as a chemoattractant for neutrophils and T lymphocytes. Severe COVID-19 patients are found to have massive inflammatory infiltrates in their lungs where the most dominant cells from innate immune response are neutrophils. These same neutrophils are the ones that induce tissue destruction ^[19]. The most dominant cells in the infiltrate that belong to the adaptive immune response were cytotoxic CD8+T cells, which can explain the depletion of T-cell count in peripheral blood. These T cells can kill the virus, but similarly to neutrophils, they can also cause tissue destruction ^[20]. Other cells found in the infiltrate were monocytes, which respond to GM-CSF and have high expression of IL-6. It is very probable that their number rises with the progression of the disease.

In addition to respiratory symptoms, severe COVID-19 patients suffer from thrombosis and pulmonary embolism and have elevated levels of fibrinogen and d-dimer. This hypercoagulable state most likely implies massive endothelial damage. Since endothelial cells comprise one-third of pulmonary cells ^[21] and they express ACE2 ^[22], the virus could penetrate them, causing their injury. Endothelial injury could cause increased vascular permeability, which can make viral penetration easier.

References

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Lidija Popović Dragonjić

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Update Date: 29 Nov 2022

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1. Introduction

2. Structure of SARS-CoV-2: Mechanism of SARS-CoV-2 Invasion into Host Cells

3. Host Response to SARS-CoV-2

References